Processes for the preparation of hydroxylamines

ABSTRACT

The present invention relates generally to novel methods for the synthesis of O-(6-pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine which is an essential reagent in the synthesis of one of the bridged erythromycin derivatives and their respective pharmaceutically acceptable salts in PCT Application WO 03/097659 A1. In particular, the present invention relates to processes and intermediates for the preparation of a compound of formula (Ia):

RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 11/205,764, filed on Aug. 17, 2005, which claims the benefit of U.S.Provisional Application No. 60/676,727, filed on May 2, 2005 and U.S.Provisional Application No. 60/696,622, filed on Jul. 5, 2005. Theentire teachings of the above applications are incorporated herein byreference.

TECHNICAL FIELD

The present invention relates generally to the processes andintermediates useful in the preparationO-(6-pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine which is a reagentin the synthesis of certain bridged erythromycin and ketolidederivatives described in U.S. Pat No. 6,878,691, U.S. Pat Pub. No.2005037982 and PCT Application WO 03/097659 A1.

BACKGROUND OF THE INVENTION

Macrolide antibiotics play a therapeutically important role,particularly with the emergence of new pathogens. Structural differencesare related to the size of the lactone ring and to the number and nature(neutral or basic) of the sugars. Macrolides are classified according tothe size of the lactone ring (12, 14, 15 or 16 atoms). The macrolideantibiotic family (14-, 15- and 16-membered ring derivatives) shows awide range of characteristics (antibacterial spectrum, side-effects andbioavailability). Among the commonly used macrolides are erythromycin,clarithromycin, and azithromycin. Macrolides possessing a 3-oxo moietyin place of the 3-cladinose sugar are known as ketolides and have shownenhanced activity towards gram-negative bacteria and macrolide resistantgram-positive bacteria. The search for macrolide compounds which areactive against MLSB-resistant strains (MLSB=Macrolides-Lincosamides-typeB Streptogramines) has become a major goal, together with retaining theoverall profile of the macrolides in terms of stability, tolerance andpharmacokinetics.

Recently PCT Application WO 03/095466 A1, published Nov. 20, 2003 andPCT Application WO 03/097659 A1, published Nov. 27, 2003 disclose aseries of bicyclic erythromycin derivatives.

SUMMARY OF THE INVENTION

The present invention provides methods for preparing compounds ofFormula I:

A most preferred embodiment of a compound of formula I isO-(6-pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine having the formulaIa:

In one embodiment of the invention, pyridyl derivatives of formulae Iare reacted with pyrazole in the presence of acids, bases or metalliccatalysts. The invention further relates to increasing product yield anddecreasing process steps for intermediate and large scale productionO-(6-pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine. Compounds ofFormula I and particularly,O-(6-pyrazole-1-yl-pyridin-3-ylmethyl)-hydroxylamine is particularlyuseful as a reagent in the synthesis of EP13420 which has the followingformula:

DETAILED DESCRIPTION OF THE INVENTION

In a first embodiment, the present invention provides a process for thepreparation of compounds of formulae (I);

wherein R₁ and R₂ are each independently selected from:

-   -   (a) hydrogen; or    -   (b) NH₂;        or one of R₁ or R₂ is a hydrogen and the other is selected from:    -   (a) C(O)R₃, where R₃ is C₁-C₆ alkyl, optionally substituted with        one or more substituents selected from aryl, substituted aryl,        heteroaryl, or substituted heteroaryl;    -   (b) C(O)OR₃, where R₃ is as previously defined; or.

-   -    wherein A and B are each independently hydrogen, a substituted        or unsubstituted aliphatic group, a substituted or unsubstituted        cyclic group, a substituted or unsubstituted heterocyclic group,        a substituted or unsubstituted aryl group, a substituted or        unsubstituted alicyclic group, or a substituted or unsubstituted        heteroaryl group; or A and B taken together with the carbon to        which they are attached form a cyclic moiety selected from:        aryl, substituted aryl, heterocyclic, substituted heterocyclic,        alicyclic, or substituted alicyclic;        alternatively, R₁ and R₂ are taken together with the nitrogen        atom to which they are attached to form N═C(R₄)(R₅), where R₄        and R₅ are each independently selected from a substituted or        unsubstituted aliphatic group, a substituted or unsubstituted        cyclic group, a substituted or unsubstituted heterocyclic group,        a substituted or unsubstituted aryl group, a substituted or        unsubstituted alicyclic group, or a substituted or unsubstituted        heteroaryl group;        said process comprising one or more of the following steps:

-   (1) treating 2-chloro-5-chloromethyl-pyridine with compounds of    formula R₁R₂NOH wherein R1 and R2 are as previously defined in the    presence of base to yield compounds of formulae (II):

-   (2) reacting pyrazole with compound of formulae (II) in the presence    of acid, base and metallic catalyst to provide compound of formula    (I):

Optionally, the process may further comprise the step of hydrolyzing thecompound of formula I with a base or an acid in a protogenic organicsolvent or aqueous solution, to yield a preferred compound of theinvention, O-(6-pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine, havingthe formulae (Ia):

In a second embodiment, the present invention provides a process for thepreparation of a compound of formulae (I);

wherein R₁ and R₂ are each independently selected from

-   -   (a) hydrogen; or    -   (b) NH₂;        or one of R₁ or R₂ is a hydrogen and the other is selected from:    -   (a) C(O)R₃, where R₃ is C₁-C₆ alkyl, optionally substituted with        one or more substituents selected from aryl, substituted aryl,        heteroaryl, or substituted heteroaryl;    -   (b) C(O)OR₃, where R₃ is as previously defined; or

-   -    wherein A and B are each independently hydrogen, a substituted        or unsubstituted aliphatic group, a substituted or unsubstituted        cyclic group, a substituted or unsubstituted heterocyclic group,        a substituted or unsubstituted aryl group, a substituted or        unsubstituted alicyclic group, or a substituted or unsubstituted        heteroaryl group; or A and B taken together with the carbon to        which they are attached to form a cyclic moiety selected from:        aryl, substituted aryl, heterocyclic, substituted heterocyclic,        alicyclic, or substituted alicyclic;        alternatively, R₁ and R₂ are taken together with the nitrogen        atom to which they are attached to form N═C(R₄)(R₅), where R₄        and R₅ are each independently selected from a substituted or        unsubstituted aliphatic group, a substituted or unsubstituted        cyclic group, a substituted or unsubstituted heterocyclic group,        a substituted or unsubstituted aryl group, a substituted or        unsubstituted alicyclic group, or a substituted or unsubstituted        heteroaryl group;        said process comprising one or more of the following steps:

-   (1) treating (6-chloro-pyridin-3-yl)-methanol with a suitable    hydroxyl protecting reagent to form compounds of formulae (IV):

-   -   where Rp is a hydroxyl protecting group;

-   (2) reacting pyrazole with compounds of formulae (IV) in the    presence of base to give compound of the following formula V:

-   (3) deprotecting the hydroxyl protecting group of formula (V) and    halogenating the corresponding compound with a chlorinating reagent    to provide a compound of formula (VI):

-   (4) treating compounds of formulae (VI) with compounds of formula    R₁R₂NOH wherein R1 and R2 are as previously defined, in the presence    of base, followed by hydrolysis to provide compounds of formula (I).

Optionally, the process may further comprise the step of hydrolyzing thecompound of formula I with a base or an acid in a protogenic organicsolvent or aqueous solution, to yield a preferred compound of theinvention, O-(6-pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine, havingthe formulae (Ia):

In yet another embodiment of the invention a process is provided thatcomprises one or more of the following steps:

-   (1) treating (6-chloro-pyridin-3-yl)-methanol with pyrazole in the    presence of any of the following: an acid catalyst in organic    solvent, preferably in an aprotic solvent; a neat organic acid; or a    base with a catalyst such as copper(I) salt or other transition    metal derivatives combined with 1,2-diamino derivatives, preferably    in an aprotic solvent; to form a compound of formula III,    (6-Pyrazole-1-yl-pyrind-3-yl)-methanol:

-   (2) halogenating the compound of formula III with a chlorinating    reagent to provide a compound of formula (VI):

-   (3) reacting at least one compound of the formula R₁R₂NOH wherein R₁    and R₂ are as previously defined, with the compound of formula VI to    form a compound of formula I.

Optionally, the process may further comprise the step of hydrolyzing thecompound of formula I with a base or an acid in a protogenic organicsolvent or aqueous solution, to yield a preferred compound of theinvention, O-(6-pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine, havingthe formulae (Ia):

The above processes, as well as other processes depicted in thisapplication react either a pyrazole, hydroxylamine or other compoundwith a chloropyridine or a substituted chloroalkane (e.g., a substitutedpyridinylmethyl chloride). In these reactions, the chloride acts as aleaving group. In yet another set of embodiments of the invention, otherleaving groups can be used in place of the chlorine. Examples of leavinggroups include, without limitation, halo groups, e.g., bromine, orsulfonates, e.g., tosylate, mesylate, nosylate, and triflate. In thisembodiment, the Cl of the formula set forth above can be replaced with aLG wherein LG is a leaving group.

DEFINITIONS

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

An “aliphatic group” is non-aromatic moiety that may contain anycombination of carbon atoms, hydrogen atoms, halogen atoms, oxygen,nitrogen or other atoms, and optionally contain one or more units ofunsaturation, e.g., double and/or triple bonds. An aliphatic group maybe straight chained, branched or cyclic and preferably contains betweenabout 1 and about 24 carbon atoms, more typically between about 1 andabout 12 carbon atoms. In addition to aliphatic hydrocarbon groups,aliphatic groups include, for example, polyalkoxyalkyls, such aspolyalkylene glycols, polyamines, and polyimines, for example. Suchaliphatic groups may be further substituted.

Suitable aliphatic or aromatic substituents include, but are not limitedto, —F, —Cl, —Br, —I, —OH, protected hydroxy, aliphatic ethers, aromaticethers, oxo, —NO₂, —CN, —C₁-C₁₂-alkyl optionally substituted withhalogen (such as perhaloalkyls), C₂-C₁₂-alkenyl optionally substitutedwith halogen, -C₂-C₁₂-alkynyl optionally substituted with halogen, —NH₂,protected amino, —NH-C₁-C₁₂-alkyl, —NH-C₂-C₁₂-alkenyl,—NH-C₂-C₁₂-alkenyl, —NH-C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl,—NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino,—O-C₁-C₁₂-alkyl, —O-C₂-C₁₂-alkenyl, —O-C₂-C₁₂-alkynyl,—O-C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—C(O)-C₁-C₁₂-alkyl, —C(O)-C₂-C₁₂-alkenyl, —C(O)-C₂-C₁₂-alkynyl,—C(O)-C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl, —CONH₂, —CONH-C₁-C₁₂-alkyl,—CONH-C₂-C₁₂-alkenyl, —CONH-C₂-C₁₂-alkynyl, —CONH-C₃-C₁₂-cycloalkyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl, —CO₂-C₁-C₁₂-alkyl,—CO₂-C₂-C₁₂-alkenyl, —CO₂-C₂-C₁₂-alkynyl, —CO₂-C₃-C₁₂-cycloalkyl,—CO₂-aryl, —CO₂-heteroaryl, —CO₂-heterocycloalkyl, —OCO₂-C₁-C₁₂-alkyl,—OCO₂-C₂-C₁₂-alkenyl, —OCO₂-C₂-C₁₂-alkynyl, —OCO₂-C₃-C₁₂-cycloalkyl,—OCO₂-aryl, —OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂,—OCONH-C₁-C₁₂-alkyl, —OCONH-C₂-C₁₂-alkenyl, —OCONH-C₂-C₁₂-alkynyl,—OCONH-C₃-C₁₂-cycloalkyl, —OCONH-aryl, —CONH-heteroaryl,—OCONH-heterocycloalkyl, —NHC(O)-C₁-C₁₂-alkyl, —NHC(O)-C₂-C₁₂-alkenyl,—NHC(O)-C₂-C₁₂-alkynyl, —NHC(O)-C₃-C₁₂-cycloalkyl, —NHC(O)-aryl,—NHC(O)-heteroaryl, —NHC(O)-heterocycloalkyl, —NHCO₂-C₁-C₁₂-alkyl,—NHCO₂-C₂-C₁₂-alkenyl, —NHCO₂-C₂-C₁₂-alkynyl, —NHCO₂-C₃-C₁₂-cycloalkyl,—NHCO₂-aryl, —NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,NHC(O)NH-C₁-C₁₂-alkyl, —NHC(O)NH-C₂-C₁₂-alkenyl,—NHC(O)NH-C₂-C₁₂-alkynyl, —NHC(O)NH-C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,NHC(S)NH-C₁-C₁₂-alkyl, —NHC(S)NH-C₂-C₁₂-alkenyl,—NHC(S)NH-C₂-C₁₂-alkynyl, —NHC(S)NH-C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH-C₁-C₁₂-alkyl, —NHC(NH)NH-C₂-C₁₂-alkenyl,—NHC(NH)NH-C₂-C₁₂-alkynyl, —NHC(NH)NH-C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,NHC(NH)-C₁-C₁₂-alkyl, —NHC(NH)-C₂-C₁₂-alkenyl, —NHC(NH)-C₂-C₁₂-alkynyl,—NHC(NH)-C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH-C₁-C₁₂-alkyl,—C(NH)NH-C₂-C₁₂-alkenyl, —C(NH)NH-C₂-C₁₂-alkynyl,—C(NH)NH-C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)-C₁-C₁₂-alkyl, —S(O)-C₂-C₁₂-alkenyl,—S(O)-C₂-C₁₂-alkynyl, —S(O)-C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl-SO₂NH₂, —SO₂NH-C₁-C₁₂-alkyl,—SO₂NH-C₂-C₁₂-alkenyl, —SO₂NH-C₂-C₁₂-alkynyl, —SO₂NH-C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂-C₁-C₁₂-alkyl, —NHSO₂-C₂-C₁₂-alkenyl, —NHSO₂-C₂-C₁₂-alkynyl,—NHSO₂-C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S-C₁-C₁₂-alkyl, —S-C₂-C₁₂-alkenyl, —S-C₂-C₁₂-alkynyl,—S-C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl. It is understood that the aryls, heteroaryls, alkylsand the like can be further substituted.

The terms “C₂-C₁₂ alkenyl” or “C₂-C₆ alkenyl,” as used herein, denote amonovalent group derived from a hydrocarbon moiety containing from twoto twelve or two to six carbon atoms having at least one carbon-carbondouble bond by the removal of a single hydrogen atom. Alkenyl groupsinclude, but are not limited to, for example, ethenyl, propenyl,butenyl, 1-methyl-2-buten- 1-yl, alkadienes and the like.

The term “substituted alkenyl,” as used herein, refers to a “C₂-C₁₂alkenyl” or “C₂-C₆ alkenyl” group as previously defined, substituted byone, two, three or more aliphatic substituents.

The terms “C₂-C₁₂ alkynyl” or “C₂-C₆ alkynyl,” as used herein, denote amonovalent group derived from a hydrocarbon moiety containing from twoto twelve or two to six carbon atoms having at least one carbon-carbontriple bond by the removal of a single hydrogen atom. Representativealkynyl groups include, but are not limited to, for example, ethynyl,1-propynyl, 1-butynyl, and the like.

The term “substituted alkynyl,” as used herein, refers to a “C₂-C₁₂alkynyl” or “C₂-C₆ alkynyl” group as previously defined, substituted byone, two, three or more aliphatic substituents.

The term “C₁-C₆ alkoxy,” as used herein, refers to a C₁-C₆ alkyl group,as previously defined, attached to the parent molecular moiety throughan oxygen atom. Examples of C₁-C₆-alkoxy include, but are not limitedto, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy,tert-butoxy, n-pentoxy, neopentoxy and n-hexoxy.

The terms “halo” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine and iodine.

The terms “aryl” or “aromatic” as used herein, refer to a mono- orbicyclic carbocyclic ring system having one or two aromatic ringsincluding, but not limited to, phenyl, naphthyl, tetrahydronaphthyl,indanyl, idenyl and the like.

The terms “substituted aryl” or “substituted aromatic,” as used herein,refer to an aryl or aromatic group substituted by one, two, three ormore aromatic substituents.

The term “arylalkyl,” as used herein, refers to an aryl group attachedto the parent compound via a C₁-C₃ alkyl or C₁-C₆ alkyl residue.Examples include, but are not limited to, benzyl, phenethyl and thelike.

The term “substituted arylalkyl,” as used herein, refers to an arylalkylgroup, as previously defined, substituted by one, two, three or morearomatic substituents.

The terms “heteroaryl” or “heteroaromatic,” as used herein, refer to amono-, bi- or tri-cyclic aromatic radical or ring having from five toten ring atoms of which at least one ring atom is selected from S, 0 andN; zero, one or two ring atoms are additional heteroatoms independentlyselected from S, 0 and N; and the remaining ring atoms are carbon,wherein any N or S contained within the ring may be optionally oxidized.Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl,pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl,isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and thelike. The heteroaromatic ring may be bonded to the chemical structurethrough a carbon or hetero atom.

The terms “substituted heteroaryl” or “substituted heteroaromatic,” asused herein, refer to a heteroaryl or heteroaromatic group, substitutedby one, two, three, or more aromatic substituents.

The term “alicyclic,” as used herein, denotes a monovalent group derivedfrom a monocyclic or bicyclic saturated carbocyclic ring compound by theremoval of a single hydrogen atom. Examples include, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1]heptyl, and bicyclo [2.2.2] octyl.

The term “substituted alicyclic,” as used herein, refers to an alicyclicgroup substituted by one, two, three or more aliphatic substituents.

The term “heterocyclic,” as used herein, refers to a non-aromatic 5-, 6-or 7-membered ring or a bi- or tri-cyclic group fused system, where (i)each ring contains between one and three heteroatoms independentlyselected from oxygen, sulfur and nitrogen, (ii) each 5-membered ring has0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds,(iii) the nitrogen and sulfur heteroatoms may optionally be oxidized,(iv) the nitrogen heteroatom may optionally be quatemized, (iv) any ofthe above rings may be fused to a benzene ring, and (v) the remainingring atoms are carbon atoms which may be optionally oxo-substituted.Representative heterocycloalkyl groups include, but are not limited to,[1,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl,pyridazinonyl, and tetrahydrofuryl.

The term “substituted heterocyclic,” as used herein, refers to aheterocyclic group, as previously defined, substituted by one, two,three or more aliphatic substituents.

The term “heteroarylalkyl,” as used herein, to an heteroaryl groupattached to the parent compound via a C₁-C₃ alkyl or C₁-C₆ alkylresidue. Examples include, but are not limited to, pyridinylmethyl,pyrimidinylethyl and the like.

The term “substituted heteroarylalkyl,” as used herein, refers to aheteroarylalkyl group, as previously defined, substituted by independentreplacement of one, two, or three or more aromatic substituents.

The term “alkylamino” refers to a group having the structure —NH(C₁-C₁₂alkyl).

The term “dialkylamino” refers to a grop having the structure —N(C₁-C₁₂alkyl) (C₁-C₁₂ alkyl), where C₁-C₁₂ alkyl is as previously defined.Examples of dialkylamino are, but not limited to, dimethylamino,diethylamino, methylethylamino, piperidino, and the like.

The term “alkoxycarbonyl” represents an ester group, i.e., an alkoxygroup, attached to the parent molecular moiety through a carbonyl groupsuch as methoxycarbonyl, ethoxycarbonyl, and the like.

The term “carboxaldehyde,” as used herein, refers to a group of formula—CHO.

The term “carboxy,” as used herein, refers to a group of formula —COOH.

The term “carboxamide,” as used herein, refers to a group of formula—C(O)NH(C₁-C₁₂ alkyl) or —C(O)N(C₁-C₁₂ alkyl) (C₁-C₁₂ alkyl), —C(O)NH₂,NHC(O)(C₁-C₁₂ alkyl), N(C₁-C₁₂ alkyl)C(O)(C₁-C₁₂ alkyl) and the like.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxyl groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theare described generally in T. H. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York(1999). Examples of hydroxyl protecting groups includebenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl,trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl,2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl-2-propenyl,3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl,triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl,methylthiomethyl, benzyloxymethyl, 2,2,2-triehloroethoxymethyl,2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl,trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like.Preferred hydroxyl protecting groups for the present invention areacetyl (Ac or —C(O)CH₃), benzoyl (Bz or —C(O)C₆H₅), and trimethylsilyl(TMS or —Si(CH₃)₃).

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl,trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl,2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl-2-propenyl,3-methyl- 3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl,triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl,methylthiomethyl, benzyloxymethyl, 2,2,2-triehloroethoxymethyl,2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl,trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like.Preferred hydroxyl protecting groups for the present invention areacetyl (Ac or —C(O)CH₃), benzoyl (Bz or —C(O)C₆H₅), and trimethylsilyl(TMS or —Si(CH₃)₃).

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the aredescribed generally in T. H. Greene and P. G. M. Wuts, Protective Groupsin Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).Examples of amino protecting groups include, but are not limited to,t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and thelike.

The term “protected amino,” as used herein, refers to an amino groupprotected with an amino protecting group as defined above.

The term “acyl” includes residues derived from acids, including but notlimited to carboxylic acids, carbamic acids, carbonic acids, sulfonicacids, and phosphorous acids. Examples include aliphatic carbonyls,aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphaticsulfinyls, aromatic phosphates and aliphatic phosphates.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such compounds are well known to those skilledin the art, and it will be obvious to those skilled in the art thatindividual solvents or mixtures thereof may be preferred for specificcompounds and reaction conditions, depending upon such factors as thesolubility of reagents, reactivity of reagents and preferred temperatureranges, for example. Further discussions of aprotic solvents may befound in organic chemistry textbooks or in specialized monographs, forexample: Organic Solvents Physical Properties and Methods ofPurification, 4th ed., edited by John A. Riddick et al, Vol. II, in theTechniques of Chemistry Series, John Wiley & Sons, NY, 1986.

The term “protogenic organic solvent,” as used herein, refers to asolvent that tends to provide protons, such as an alcohol, for example,methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and thelike. Such solvents are well known to those skilled in the art, and itwill be obvious to those skilled in the art that individual solvents ormixtures thereof may be preferred for specific compounds and reactionconditions, depending upon such factors as the solubility of reagents,reactivity of reagents and preferred temperature ranges, for example.Further discussions of protogenic solvents may be found in organicchemistry textbooks or in specialized monographs, for example: OrganicSolvents Physical Properties and Methods of Purification, 4th ed.,edited by John A. Riddick et al., Vol. II, in the Techniques ofChemistry Series, John Wiley & Sons, NY, 1986.

The term “oxidizing agent(s),” as used herein, refers to reagents usefulfor oxidizing the 3-hydroxyl of the macrolide ring to the 3-carbonyl.Oxidizing agents suitable in the present process are either Swernoxidation reagents (dimethyl sulfoxide and an electrophilic compoundselected from dicyclohexylcarbodiimide, acetic anhydride,trifluoroacetic anhydride, oxalyl chloride, or sulfur trioxide), DessMartin oxidation reagents, or Corey-Kim oxidation reagents. A preferredmethod of oxidation is the use of the Corey-Kim oxidation reagentsN-chlorosuccinimide-dimethyl sulfide complex.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein.

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the formulae herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995).

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and may include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds, otherunsaturation, or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers or cis- and trans-isomers. Likewise, alltautomeric forms are also intended to be included. The configuration ofany carbon-carbon double bond appearing herein is selected forconvenience only and is not intended to designate a particularconfiguration unless the text so states; thus a carbon-carbon doublebond or carbon-heteroatom double bond depicted arbitrarily herein astrans may be cis, trans, or a mixture of the two in any proportion.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable include,but are not limited to, nontoxic acid addition salts are salts of anamino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, maleic acid, tartaric acid,citric acid, succinic acid or malonic acid or by using other methodsused in the art such as ion exchange. Other pharmaceutically acceptablesalts include, but are not limited to, adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals with undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of thepresent invention. “Prodrug”, as used herein means a compound which isconvertible in vivo by metabolic means (e.g. by hydrolysis) to acompound of Formula I. Various forms of prodrugs are known in the art,for example, as discussed in Bundgaard, (ed.), Design of Prodrugs,Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4,Academic Press (1985); Krogsgaard-Larsen, et al., (ed). “Design andApplication of Prodrugs, Textbook of Drug Design and Development,Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug DeliverReviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel DrugDelivery Systems, American Chemical Society (1975); and Bernard Testa &Joachim Mayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry,Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues is covalently joined through an amide or ester bond to a freeamino, hydroxy or carboxylic acid group of a bridged erythromycin orketolide derivative synthesized using the reagents prepared inaccordance with the invention. The amino acid residues include but arenot limited to the 20 naturally occurring amino acids commonlydesignated by three letter symbols and also includes 4-hydroxyproline,hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin,beta-alanine, gamma-aminobutyric acid, citrulline homocysteine,homoserine, ornithine and methionine sulfone. Additional types ofprodrugs are also encompassed. For instance, free carboxyl groups can bederivatized as amides or alkyl esters. Free hydroxy groups may bederivatized using groups including but not limited to hemisuccinates,phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities.

Suitable concentrations of reactants used in the synthesis processes ofthe invention are 0.01M to 10M, typically 0.1M to 1M. Suitabletemperatures include −10° C. to 250° C., typically −78° C. to 150° C.,more typically −78° C. to 100° C., still more typically 0° C. to 100° C.Reaction vessels are preferably made of any material which does notsubstantial interfere with the reaction. Examples include glass,plastic, and metal. The pressure of the reaction can advantageously beoperated at atmospheric pressure. The atmospheres include, for example,air, for oxygen and water insensitive reactions, or nitrogen or argon,for oxygen or water sensitive reactions.

The term “in situ,” as used herein, refers to use of an intermediate inthe solvent or solvents in which the intermediate was prepared withoutremoval of the solvent.

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one with ordinary skill inthe art. All publications, patents, published patent applications, andother references mentioned herein are hereby incorporated by referencein their entirety.

ABBREVIATIONS

Abbreviations which may be used in the descriptions of the scheme andthe examples that follow are:

-   -   Ac for acetyl;    -   AIBN for azobisisobutyronitrile;    -   Bu₃SnH for tributyltin hydride;    -   CDI for carbonyldiimidazole;    -   dba for dibenzylidene acetone;    -   dppb for diphenylphosphino butane or        1,4-bis(diphenylphosphino)butane;    -   DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene;    -   DEAD for diethylazodicarboxylate;    -   DMAP for dimethylaminopyridine;    -   DMF for dimethyl formamide;    -   DPPA for diphenylphosphoryl azide;    -   EtOAc for ethyl acetate;    -   HPLC for high-pressure liquid chromatography;    -   MeOH for methanol;    -   NaN(TMS)₂ for sodium bis(trimethylsilyl)amide;    -   NMMO for N-methylmorpholine N-oxide;    -   Rp for hydroxyl protecting group;    -   TEA for triethylamine;    -   THF for tetrahydrofuran;    -   TPP or PPh₃ for triphenylphosphine;    -   MOM for methoxymethyl;    -   Boc for t-butoxycarbonyl;    -   Bz for benzyl;    -   Ph for phenyl;    -   POPd for dihydrogen        dichlorobis(di-tert-butylphosphinito-KP)palladate(II);    -   TBS for tert-butyl dimethylsilyl; or    -   TMS for trimethylsilyl.

All other abbreviations used herein, which are not specificallydelineated above, shall be accorded the meaning which one of ordinaryskill in the art would attach.

SYNTHETIC SCHEMES

The present invention will be better understood in connection withSchemes 1-3. It will be readily apparent to one of ordinary skill in theart that the process of the present invention can be practiced bysubstitution of the appropriate reactants and that the order of thesteps themselves can be varied.

As outlined in Scheme 1, Step A, a compound of formula (II) is preparedby adding the compound of formula (1-2) to a compound of formula (1-1),wherein R₁ and R₂ are as previously defined. The present conversionpreferably takes place in the presence of a base in an aprotic solvent.

A compound of formula (I) is prepared, as illustrated in Step B ofScheme 1, by reacting 2-chloro-5-methyl-hydroxyamine derivatives (II)with pyrazole in the presence of an acid catalyst in organic solvent,preferably in an aprotic solvent or without solvent, to provide acompound of the formula (I). In a preferred embodiment of the reaction,the reaction temperature is between 75° C. and 200° C. and the durationof the reaction is 6 to 48 hours. In a particularly preferred embodimentof the reaction, the acid is organic acid, such as acetic acid, toluenesolufonic, methyl sulfonic acid, or camphorsulfonic acid withoutadditional solvent.

In another embodiment of Scheme 1, a compound of formula (I) isprepared, as illustrated in Step B of Scheme 1, by reacting2-chloro-5-methyl-hydroxyamine derivatives (II) with pyrazole in a neatorganic acid, to provide a compound of the formula (I). In a preferredembodiment of the reaction, the reaction temperature is under a refluxtemperature of the chosen acid, and the duration of the reaction is 12to 48 hours. In a particularly preferred embodiment of the reaction, theacid is acetic acid, and the temperature is acetic acid refluxtemperature.

In another embodiment of Scheme 1, a compound of formula (I) is preparedas illustrated in Step B, by reacting 2-chloro-5-methyl-hydroxyaminederivatives (II) with pyrazole in the presence of a base with catalyst,such as copper(I) salt or other transition metal derivatives combinedwith a 1,2-diamino derivatives, preferably in an aprotic solvent, toprovide a compound of the formula (I). In a preferred embodiment of thereaction, the reaction temperature is between 25° C. and 150° C. and theduration of the reaction is less than 6 to 48 hours. In a particularlypreferred embodiment of the reaction, the base is potassium carbonateand the aprotic solvent is neat pyrazole, the catalyst is copper(II)iodide and racemic-trans-N,N′-dimethylcycloheaxane-1,2-diamine.

As outlined in Scheme 1, Step C, a compound of formula (Ia) is preparedby removal of the protecting group of R₁ and R₂ in the formula (I) undereither basic or acidic conditions, depending on the nature of R₁ and R₂,wherein R₁ and R₂ are as previously defined.

Scheme 2 describes another process of preparing compounds I and Ia,

As outlined in Scheme 2, Step A, a compound of formula (III) is preparedby adding the compound of formula (2-2) to a compound of formula (2-1).The present conversion preferably takes place in the presence of acidcatalyst or a basic catalytic system, in an aprotic solvent.

A compound of formula (III) is prepared, as illustrated in Step A ofScheme 1, by reacting 2-chloro-5- hydroxymethyl-pyridine (2-1) withpyrazole in the presence of acid catalyst in organic solvent, preferablyin an aprotic solvent, to provide a compound of the formula (III). In apreferred embodiment of the reaction, the reaction temperature isbetween 75° C. and 200° C. and the duration of the reaction is 6 to 48hours. In a particularly preferred embodiment of the reaction, the acidis organic acid, such as acetic acid, toluene solufonic, methyl sulfonicacid, or camphorsulfonic acid and the aprotic solvent is toluene.

Alternatively, a compound of formula (III) is prepared, as illustratedin Step A of Scheme 2, by reacting 2-chloro-6- hydroxymethyl-pyridine(2-1) with pyrazole in a neat organic acid, to provide a compound of theformula (III). In a preferred embodiment of the reaction, the reactiontemperature is under a reflux temperature of the chosen acid, and theduration of the reaction is 12 to 48 hours. In a particularly preferredembodiment of the reaction, the acid is acetic acid, and the temperatureis acetic acid reflux temperature.

Alternatively, a compound of formula (III) is prepared, as illustratedin Step A of Scheme 2, by reacting 2-chloro-5- hydroxymethyl-pyridine(2-1) with pyrazole in in the presence of a base with catalyst, such ascopper(I) salt or other transition metal derivatives combined with a1,2-diamino derivatives, preferably in an aprotic solvent, to provide acompound of the formula (III). In a preferred embodiment of thereaction, the reaction temperature is between 25° C. and 150° C. and theduration of the reaction is less than 6 to 48 hours. In a particularlypreferred embodiment of the reaction, the base is potassium carbonateand the aprotic solvent is neat pyrazole, the catalyst is copper(I)iodide and racemic-trans-N,N′-dimethylcycloheaxane-1,2-diamine.

As outlined in Scheme 2, Step B, a compound of Formula (VI) is preparedby reacting of compound (III) with a chlorinating reagent.

A compound of formula (I) is prepared by adding a compound of formula(2-3), to a compound of formula (VI), as illustrated in Step C, whereinR₁ and R₂ are as previously defined. The present conversion preferablytakes place in an aprotic solvent in the presence of a base.

A compound of formula Ia may be prepared from a compound of formula I asoutlined in Scheme 1.

Scheme 3 describes an additional process of preparing compounds I andIa.

As illustrated in Scheme 3, Step A, a compound of formula (IV) isprepared by first reacting 2-chloro-5-hydroxymethyl-pyridne (3-1) with ahydroxyl protecting reagent Rp-X, wherein, Rp is previously defined andX is a leaving group, in the presence of a base, preferably in anaprotic solvent, to provide a compound of the formula (IV).

As outlined in Scheme 3, Step B, a compound of formula (V) is preparedby adding pyrazole to a compound of formula (IV). The present conversionpreferably takes place in the same conditions as described in Scheme 2,Step A, with different starting material of formula (IV).

A compound of formula (III) is prepared, as illustrated in Step C ofScheme 3, by deprotecting the compound of formula (V) with acid or basein an aprotic organic solvent or an aqueous mixture thereof.

The compound of formula VI is prepared by reacting the compound offormula III with a chlorinating reagent. The compound of formula I isprepared from the compound of formula VI by reacting the compound offormula VI with at least one compound of formula R₁R₂NOH wherein R₁ andR₂ are as previously defined, in the presence of base, optionallyfollowed by hydrolysis to provide compounds of formula Ia.

All references cited herein, whether in print, electronic, computerreadable storage media or other form, are expressly incorporated byreference in their entirety, including but not limited to, abstracts,articles, journals, publications, texts, treatises, internet web sites,databases, patents, and patent publications.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Example 1 Preparation of 2-chloro-5-pyridyl-N-methoxy succinimide (IIb)

To a 5L-three neck flask equipped with a mechanic stirrer, heatingmantle with temperature controller and a gas outlet, were chargedN-hydroxysuccinimide (426 g, 3.7 mol), 2-chloro-5-chloromethylpyridine(500 g, 3.1 mol) and anhydrous DMF (1 L). The mixture was stirred for 5min when inner temperature dropped to 8.5° C. Anhydrous K₂CO₃ (640 g,4.6 mol) was charged in one portion followed by anhydrous DMF (0.5 L).It was stirred for 5 min when inner temperature raised to 15.5° C. Themixture was heated to 70° C. (preset) within 30 min but the temperaturecontinued to rise to 89° C. over 1 h of reaction period, during which alot of gas was evolved and the reaction was finished as judged by MS andTLC, or simply the termination of gas-evolving. It was cooled down toroom temperature, poured into water (6 L) with mechanic stirring. Theinsoluble was collected by filtration and washed with water (1.5 L),air-dried for 60 h to give the desired product as an off-white powder(364 g, 49%). ESIMS m/e (M+H)⁺: 241. ¹H NMR (500 MHz, CDCl₃): 8.44 (s, 1H), 7.95 (d, 1 H, ³J=8.5 Hz), 7.41 (d, 1 H, ³J=8.0 Hz), 5.14 (s, 2 H),2.73 (s, 4 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ 170.8, 152.6, 150.2,140.2, 128.2, 124.4, 74.9, 25.4.

Example 2 Preparation of 2-chloro-5-pyridyl-N-methoxy acetonimide (IIc)

Sodium hydride (60 wt %, 485 mg, 12 mmol, 1.2 eq) was added portion-wiseto a DMF (6 ml) solution of propan-2-one oxime (886 mg, 12 mmol, 1.2eq). To the resulting white foaming suspension was added a DMF (3.5 ml)solution of 2-chloro-5-chloromethyl-pyridine (1. 64 g, 10 mmol). Afterstirring for 4 hours at room temperature, the reaction mixture wasdiluted with 30 ml ethyl acetate. The organic solution was washed withwater (3×50 ml), dried over sodium sulfate and concentrated. Columnchromatography (hexanes) of the residue afforded the product as a lightyellow oil 1.8 g (yield: 90%). MS-ESI m/z 198.98 (M+H)⁺; ¹H NMR (CDCl₃)δ 8.39 (s, 1H), 7.67 (d, 1H), 7.33 (d, 1H), 5.05 (s, 2H), 1.92 (s, 3H),1.90 (s, 3H) ppm.

Example 3 Preparation of 2-(1-pyrazolyl)-5-pyridyl-N-methoxy succinimide(Ib)

Procedure-1

Starting material (IIa, 2.4 g, 10 mmol) and pyrazole (2.0 g, 29.4 mmol,2.9 eq) were mixed with p-toluenesulfonic acid (190 mg, 1.0 mmol, 10 mol%). The resulting mixture was heated to 110° C. stirred for 10 hours.After cooling down, the residue was dissolved in CH₂Cl₂ (150 ml) andwashed with half saturated aqueous sodium bicarbonate (50 ml). Theorganic phase was separated, dried over sodium sulfate and concentrated.Crystallization (CH₂Cl₂:hexanes, 1:2, 100 ml) afforded the product as awhite crystalline solid 2.4 g (yield: 89%, purity >95% by ¹H NMR).MS-ESI m/z 273.08 (M+H)⁺; ¹H NMR (CDCl₃) δ 8.58 (s, 1H), 8.46 (s, 1H),8.03 (s, 2H), 7.76 (s, 1H), 6.45 (s, 1H), 5.18 (s, 2H), 2.68 (s, 4H)ppm, ¹³C NMR (CDCl₃) δ 171.2, 149.4, 142.7, 140.7, 127.5, 127.0, 112.5,108.3, 75.7, 25.7 ppm.

Example 4 Preparation of 2-(1-pyrazolyl)-5-pyridyl-N-methoxy succinimide(Ib)

Procedure-2

Starting material (224 mg, 0.93 mmol), pyrazole (74.5 mg, 1.09 mmol)were dissolved in acetic acid (1.4 ml) and stirred at 105° C. for 65hours. After cooling down, the mixture was diluted with 10 ml ethylacetate and carefully basified with saturated aqueous sodium bicarbonatesolution to pH 8-9. The organic phase was separated, dried over sodiumsulfate and concentrated. Column chromatography (EtOAc:hexanes, 1:1) ofthe residue afforded the product as an off-white solid 203 mg (yield:80%). MS-ESI m/z 273.08 (M+H)⁺; ¹H NMR (CDCl₃) δ 8.58 (s, 1H), 8.46 (s,1H), 8.03 (s, 2H), 7.76 (s, 1H), 6.45 (s, 1H), 5.18 (s, 2H), 2.68 (s,4H) ppm, ¹³C NMR (CDCl₃) δ 171.2, 149.4, 142.7, 140.7, 127.5, 127.0,112.5, 108.3, 75.7, 25.7 ppm.

Example 5 Preparation of 2-(1-pyrazolyl)-5-pyridyl-N-methoxy acetonimide(Ic)

Copper(I) iodide (30 mg, 0.16 mmol, 13mol %), pyrazole (290 mg, 4.26mmol, 3.5 eq), potassium carbonate (496 mg, 3.60 mmol, 3.0 eq), startingmaterial (240 mg, 1.20 mmol) andrac-trans-N,N′-dimethylcyclohexane-1,2-diamine (65 mg, 0.46 mmol, 38mol%) were mixed together and stirred at 110° C. for 36 hours. Aftercooling down, the mixture was dissolved in ethyl acetate and water (1:1,v/v, 10 ml). The organic phase was separated, dried over sodium sulfateand concentrated. Column chromatography (EtOAc:hexanes, 1:1) of theresidue afforded the product as a light brown oil 220 mg (yield: 80%).MS-ESI m/z 231.05 (M+H⁺.

Example 6 Preparation of (6-Pyrazol-1-yl-pyridin-3-yl)-methanol (III)

Copper(I) iodide (65 mg, 0.34 mmol, 22mol %), pyrazole (411 mg, 6.04mmol, 3.8 eq), potassium carbonate (705 mg, 5.10 mmol, 3.2 eq),(6-Chloro-pyridin-3-yl)-methanol (227 mg, 1.58 mmol) andrac-trans-N,N′-dimethylcyclohexane-1,2-diamine (92 mg, 0.65 mmol, 41mol%) were mixed together and stirred at 110° C. for 44 hours. Aftercooling down, the mixture was dissolved in ethyl acetate and water (1:1,v/v, 10 ml). The organic phase was separated, dried over sodium sulfateand concentrated. Column chromatography (EtOAc:hexanes, 1:1) of theresidue afforded the product as a light brown oil 292 mg (correctedyield: 95%), which was good for the next reaction although containing 10wt % pyrazole by ¹H NMR. MS-ESI m/z 175.97 (M+H)⁺; ¹H NMR (CDCl₃) δ 8.58(s, 1H), 8.39 (s, 1H), 7.95 (d, 1H), 7.84 (d, 1H), 7.73 (s, 1H), 6.46(s, 1H), 3.74 (s, 2H) ppm.

Example 7 Preparation of 5-Chloromethyl-2-pyrazol- 1-yl-pyridine (IV)

To a solution of alcohol (III) (10.5 g, 59.9mmol) in CH₂Cl₂ (150ml),SOCl₂ (36 g, 22 ml, 299.6 mmol) was added and the resulting reactionmixture was stirred at room temperature for a period of between 12 to 18hours. The excess SOC₂ was quenched with saturated aqueous NaHCO₃. Theresulting mixture was extracted with CH₂Cl₂ and washed with brine.Removal of solvent gave a compound of formulae (11.15 g, 95% yield) as awhite solid. MS-ESI=194.06, 196.06, ¹H NMR (ppm): 8.59(H3′, d), 8.43(H6,d), 8.03(H2, d), 7.89(H3, dd), 7.78(H5′, s), 6.50(H4′, t), 4.65(—CH2—).

Example 8 Preparation of 2-(1-pyrazolyl)-5-pyridyl-N-methoxy succinimide(Ib) via 5-Chloromethyl-2-pyrazol- 1-yl-pyridine (IV)

DBU(1.55 mL, 10.36 mmol) was added to a solution of N-hydroxysuccinimide(894 mg, 7.77 mmol) in 26 mL of DMF at 0° C. and stirred for 10 minfollowed by the addition chlorinated pyrazole-pyridine (compound IV, 1g, 5.18 mmol). The reaction mixture was stirred for 4 hrs at roomtemperature. The resulting mixture was diluted with EtOAc; washed withsaturated aqueous NaHCO₃ and brine. The combined organic layers driedover Na₂SO₄, filtered and evaporated in vacuo to yield 1.36 g(96%) ofcompound (Ib) as off-white powder. MS-ESI m/z 273.08 (M+H)⁺; ¹H NMR(CDCl₃) δ 8.58 (s, 1H), 8.46 (s, 1H), 8.03 (s, 2H), 7.76 (s, 1H), 6.45(s, 1H), 5.18 (s, 2H), 2.68 (s, 4H) ppm, ¹³C NMR (CDCl₃) δ 171.2, 149.4,142.7, 140.7, 127.5, 127.0, 112.5, 108.3, 75.7, 25.7 ppm.

The compound (Ib) can also be prepared according to the experimentalprocedure described in example 1.

Example 9 Preparation of 2-(1-pyrazolyl)-5-pyridyl-N-methoxy acetonimide(Ic)

The experimental procedure is similar to the procedure described inexample 2. MS-ESI m/z 231.05 (M+H)⁺.

Example 10 Preparation ofO-(6-Pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine (Ia) via2-(1-pyrazolyl)-5-pyridyl-N-methoxy succinimide (Ib)

Starting material (2.0 kg, 7.3 mol) was dissolved in methanol (30 L).Hydrazine monohydrate (0.72 L, 14.9 mol, 2.0 eq) was added and thereaction mixture was stirred at 45° C. for 2.5 hours. After coolingdown, the reaction mixture was diluted with water (8 L) and then wasextracted with IPAC (3×8 L). The organic phase was combined, washed withhalf saturated aqueous sodium bicarbonate and concentrated.Crystallization (IPAC:heptane, 3:4, 7 L) afforded the product was awhite crystalline solid (yield: 84%). MS-ESI m/z 191.09 (M+H)⁺; ¹H NMR(CDCl₃) δ 8.56 (d, 1H), 8.39 (d, 1H), 7.98 (d, 2H), 7.83 (dd, 1H), 7.74(d, 1H), 6.47 (dd, 1H), 5.48 (s, 2H), 4.70 (s, 2H) ppm; ¹³C NMR(CDCl₃) δ151.4, 148.4, 142.3, 139.3, 131.1, 127.3, 112.2, 108.1, 74.8 ppm.

Although the invention has been described in detail with respect tovarious preferred embodiments it is not intended to be limited thereto,but rather those skilled in the art will recognize that variations andmodifications may be made therein which are within the spirit of theinvention and the scope of the appended claims.

1. A process for the synthesis of a compound of formula (I)

wherein R₁ and R₂ are each independently selected from: (a) hydrogen; or(b) NH₂; or one of R₁ or R₂ is a hydrogen and the other is selectedfrom: (a) C(O)R₃, where R₃ is C₁-C₆ alkyl, optionally substituted withone or more substituents selected from aryl, substituted aryl,heteroaryl, or substituted heteroaryl; (b) C(O)OR₃, where R₃ is aspreviously defined; or

(c) wherein A and B are each independently hydrogen, a substituted orunsubstituted aliphatic group, a substituted or unsubstituted cyclicgroup, a substituted or unsubstituted heterocyclic group, a substitutedor unsubstituted aryl group, a substituted or unsubstituted alicyclicgroup, or a substituted or unsubstituted heteroaryl group; or A and Btaken together with the carbon to which they are attached form a cyclicmoiety selected from: aryl, substituted aryl, heterocyclic, substitutedheterocyclic, alicyclic, or substituted alicyclic; alternatively, R₁ andR₂ are taken together with the nitrogen atom to which they are attachedto form N═C(R₄)(R₅), where R₄ and R₅ are each independently selectedfrom a substituted or unsubstituted aliphatic group, a substituted orunsubstituted cyclic group, a substituted or unsubstituted heterocyclicgroup, a substituted or unsubstituted aryl group, a substituted orunsubstituted alicyclic group, or a substituted or unsubstitutedheteroaryl group said process comprising: (1) treating(6-chloro-pyridin-3-yl)-methanol with a hydroxyl protecting reagent toform a compound of formula (IV):

where Rp is a hydroxyl protecting group. (2) reacting pyrazole with thecompound of formulae (IV) in the presence of base to give compound ofthe following formula V:

(3) deprotecting the hydroxyl protecting group of formulae (V) andhalogenating the resulting compound with a chlorinating reagent toprovide a compound of formula (VI):

(4) treating the compound of formula (VI) with a compound of formulaR₁R₂NOH in the presence of base, to provide a compound of formula (I).2. The process of claim 1 further comprising the step of hydrolyzing thecompound of formula I with a base or an acid in a protogenic organicsolvent or aqueous solution, to yield a compound of formula (Ia),O-(6-Pyrazol-1-yl-pyridin-3- ylmethyl)-hydroxylamine:


3. A process for preparing a compound of formula (I):

wherein R₁, R₂, R₃, R4, R₅, A, and B are previously defined in claim 1said process comprising: (1) reacting pyrazole with(6-chloro-pyridin-3-yl)-methanol in the presence of: (a) an organic acidcatalyst; (b) an organic acid media; or (c) a metallic catalyst andbase; to form a compound of formula III

(2) halogenating the compound of formula III with a chlorinating reagentto provide a compound of formula (VI):

(3) reacting a compound of the formula R₁R₂NOH wherein R₁ and R₂ are aspreviously defined in claim 1, with the compound of formula VI to form acompound of formula I:


4. The process of claim 3 further comprising the step of hydrolyzing thecompound of formula I with a base or an acid in a protogenic organicsolvent or aqueous solution, to yield a compound of formula (Ia),O-(6-Pyrazol-1-yl-pyridin-3- ylmethyl)-hydroxylamine.
 5. The process ofclaim 3, wherein step 1 comprises reacting pyrazole with (6-Chloro-pyridin-3-yl)-methanol in the presence of toluene sulfonic acidto provide (6- Pyrazol-1-yl-pyridin-3-yl)-methanol.
 6. The process ofclaim 3, wherein step 1 comprises reacting pyrazole with (6-Chloro-pyridin-3-yl)-methanol in acetic acid to provide(6-Pyrazol-1-yl-pyridin-3-yl)- methanol.
 7. The process of claim 3,wherein step 1 comprises reacting pyrazole with (6-Chloro-pyridin-3-yl)-methanol in the presence of Cul and trans-N,N′-dimethylcyclohexane-1,2-diamine to provide(6-Pyrazol-1-yl-pyridin-3-yl)-methanol.
 8. The process of claim 3,wherein step 2 comprises reacting thionyl chloride with(6-Pyrazol-1-yl-pyridin-3-yl)-methanol to provide5-Chloromethyl-2-pyrazol- 1-yl- pyridine.
 9. The process of claim 3,wherein step 3 comprises reacting N- hydroxysuccinimide with5-Chloromethyl-2-pyrazol-1-yl-pyridine in the presence of DBU to provide2-(1-pyrazolyl)-5-pyridyl-N-methoxy succinimide.
 10. The process ofclaim 3, wherein step 3 comprises reacting propan-2-one oxime with5-Chloromethyl-2-pyrazol-1yl-pyridine in the presence of sodium hydrideto provide 2-(1-pyrazolyl)-5-pyridyl-N-methoxy acetonimide.
 11. Theprocess of claim 4 comprising reacting hydrazine with 2-(1-pyrazolyl)-5-pyridyl-N-methoxy succinimide in methanol to provideO-(6-Pyrazol-1-yl-pyridin-3- ylmethyl)-hydroxylamine.
 12. The process ofclaim 4 comprising reacting sulforic acid with 2-(1-pyrazolyl)-5-pyridyl-N-methoxy acetonimide in methanol to provideO-(6-Pyrazol-1-yl-pyridin-3- ylmethyl)-hydroxylamine.
 13. A process forpreparing a compound of formula (I):

wherein R₁ and R₂ are each independently selected from: (a) hydrogen; or(b) NH₂; or one of R₁ or R₂ is a hydrogen and the other is selectedfrom: (c) C(O)R₃, where R₃ is C₁-C₆ alkyl, optionally substituted withone or more substituents selected from aryl, substituted aryl,heteroaryl, or substituted heteroaryl; (d) C(O)OR₃, where R₃ is aspreviously defined; or

(e) wherein A and B are each independently hydrogen, a substituted orunsubstituted aliphatic group, a substituted or unsubstituted cyclicgroup, a substituted or unsubstituted heterocyclic group, a substitutedor unsubstituted aryl group, a substituted or unsubstituted alicyclicgroup, or a substituted or unsubstituted heteroaryl group; or A and Btaken together with the carbon to which they are attached form a cyclicmoiety selected from: aryl, substituted aryl, heterocyclic, substitutedheterocyclic, alicyclic, or substituted alicyclic; alternatively, R₁ andR₂ are taken together with the nitrogen atom to which they are attachedto form N═C(R4)(R₅), where R4 and R₅ are each independently selectedfrom a substituted or unsubstituted aliphatic group, a substituted orunsubstituted cyclic group, a substituted or unsubstituted heterocyclicgroup, a substituted or unsubstituted aryl group, a substituted orunsubstituted alicyclic group, or a substituted or unsubstitutedheteroaryl group said process comprising: (1) treating2-LG-5-LG-methyl-pyridine with compounds of formula R₁R₂NOH wherein R₁and R₂ are as previously defined and LG is a leaving group, in thepresence of base to yield compounds of formulae (II):

(2) reacting pyrazole with compound of formulae (II) in the presence of:(a) an organic acid catalyst; (b) an organic acid media; or (c) ametallic catalyst and base; to provide compound of formulae (I)


14. A process for preparing a compound of formula (I):

wherein R₁, R₂, R₃, R4, R₅, A, and B are previously defined in claim 1said process comprising: (1) reacting pyrazole with(6-LG-pyridin-3-yl)-methanol, wherein LG is a leaving group, in thepresence of: (a) an organic acid catalyst; (b) an organic acid media; or(c) a metallic catalyst and base; to form a compound of formula III

(2) substituting the compound of formula III with a reagent to provide acompound of formula (VI):

(3) reacting a compound of the formula R₁R₂NOH wherein R₁ and R₂ are aspreviously defined in claim 1, with the compound of formula VI to form acompound of formula I: